This Gastrointestinal SPORE application is being submitted by the Vanderbilt-Ingram Comprehensive Cancer Center (VICCC) and its affiliated institutions. This proposal is from a group of basic science researchers and clinical investigators with long-standing collaborative interactions that have resulted in significant NCI extramural funding. In this proposal, we apply the translational research strengths of the VICCC and its affiliated institutions towards reducing the incidence, morbidity and mortality of colorectal cancer by focusing on established (EGF receptor and cyclooxygenase-2), promising (p120) and to-be-identified molecular targets for prevention and therapy. We propose five projects. In Project 1, we will examine molecular correlates of EGF receptor blockade in an ECOG-approved Phase II trial of ZD 1839. In parallel with this, we will use polarizing colon cancer cells in vitro to evaluate ways in which blockade of the EGF receptor axis can be optimized. In Project 2, we will evaluate combined blockade of the EGF receptor signaling pathway and cyclooxygenase-2 in Phase I and, subsequently, Phase II trials in patients with colorectal cancer. These trials will be complemented by genetic studies to examine the importance and interaction of these two pathways in three mouse models of intestinal cancer. Project 3 is designed to utilize DNA microarray and imaging mass spectrometry to identify and, ultimately, predict rectal cancer patients most likely to respond to neoadjuvant chemoradiotherapy. Project 4 will examine the role of p120-a protein first identified by Vanderbilt investigators-in colorectal metastasis. Project 5 is designed to test and identify markers for adenoma recurrence that could eventually serve in the early detection or prevention of colorectal cancer. To support these research projects, we propose six cores: administrative, tissue, clinical trials, emerging Technologies, biostatistics and biomedical informatics. The proposed developmental (pilot) research and career development programs are tightly integrated with established institutional initiatives that have documented track records of identifying and funding promising projects and individuals. We will use these established mechanisms to fund gastrointestinal cancer-targeted pilot projects and to support career development. The strong institutional commitment from both VICCC and Vanderbilt University Medical Center to the success of this program is outlined in the application and supporting documents. We believe that the projects, cores, pilot projects and career development awards outlined in this application will lead to major improvements in the prevention, diagnosis and treatment of colorectal cancer.